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CHIESI HELLAS


SANOFI

Identification of Telmisartan as a Unique Angiotensin II Receptor Antagonist With Selective PPAR–Modulating Activity

Stephen C. Benson, Harrihar A. Pershadsingh, Christopher I. Ho, Amar Chittiboyina, Prashant Desai, Michal Pravenec, Nianning Qi, Jiaming Wang, Mitchell A. Avery, Theodore W. Kurtz

Abstract

The metabolic syndrome is a common precursor of cardiovascular disease and type 2 diabetes that is characterized by the clustering of insulin resistance, dyslipidemia, and increased blood pressure. In humans, mutations in the peroxisome proliferator-activated receptor-_ (PPAR_) have been reported to cause the full-blown metabolic syndrome, and drugs that activate PPAR_ have proven to be effective agents for the prevention and treatment of insulin resistance and type 2 diabetes. Here we report that telmisartan, a structurally unique angiotensin II receptor antagonist used for the treatment of hypertension, can function as a partial agonist of PPAR_; influence the expression of PPAR_ target genes involved in carbohydrate and lipid metabolism; and reduce glucose, insulin, and triglyceride levels in rats fed a high-fat, high-carbohydrate diet.

None of the other commercially available angiotensin II receptor antagonists appeared to activate PPAR_ when tested at concentrations typically achieved in plasma with conventional oral dosing. In contrast to ordinary antihypertensive and antidiabetic agents, molecules that can simultaneously block the angiotensin II receptor and activate PPAR_ have the potential to treat both hemodynamic and biochemical features of the metabolic syndrome and could provide unique opportunities for the prevention and treatment of diabetes and cardiovascular disease in high-risk populations. (Hypertension. 2004;43:1-10.)

Key Words: receptors, angiotensin II _ angiotensin II _ renin-angiotensin system _ insulin resistance _ losartan

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